M. Ono et al. (Bioorganic & Medicinal Chemistry 16 (2008) 6867-6872) describe certain beta-amyloid probes based on 3,5-diphenyl-1,2,4-oxadiazoles.
US 2007/0276034 discloses certain bis- and tris-dihydroxyaryl compounds and their methylenedioxy analogs and pharmaceutically acceptable esters, which are allegedly suitable for treating synucleinopathies.
WO 2008/131148 describes specific diphenyl-heteroaryl derivatives and their use for binding and imaging amyloid plaques.
Heterocyclic compounds which are useful as NURR-1 activators are disclosed in WO 2004/072050.
Radiolabeled ethylene glycol or polyethylene glycol is used as a labelling group on compounds that can be useful for imaging tissues in WO 2007/002540.
WO 98/17652 describes certain oxadiazole derivatives that a stated to be suitable for treating neurodegenerative disorders and cerebral ischaemia.
A large number of neurological and neurodegenerative diseases are known, many of which are presently not curable. These diseases include medical conditions such as Parkinson's disease, Chorea Huntington, Hallervorden-Spatz disease, Alzheimer's disease, senile dementia, Creutzfeldt-Jakob disease, artheriosclerotic dementia, cerebral thrombangitis obliterans, dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and many others.
Prion diseases, which include diseases such as Creutzfeldt-Jakob disease (CJD), scrapie and bovine spongiform encephalopathy (BSE) are pathologically characterized by a spongiform degeneration of the brain. Prion diseases are caused by an unconventional infectious agent which consists primarily of the misfolded, aggregated, beta-sheet rich PrPSc isoform of the membrane glycoprotein PrPC.
Prion diseases have caused a major concern in regard to public health due to the emergence of BSE. Scientific evidence suggests that BSE has been transmitted to humans causing a new variant of Creutzfeldt-Jakob disease (vCJD) (Will et al. 1996, Bruce et al. 1997). It is not known how many people are currently incubating the disease and will be affected by vCJD in the future. The available evidence does not exclude an impending epidemic affecting a large number of patients (Andrews et al. 2000). This heightens the need to develop effective therapeutics in addition to implementing measures preventing further spread of the disease. In addition, recent evidence suggests that secondary transmission by blood transfusion may occur (LLewelyn et al., 2004).
The central event in the pathogenesis of prion diseases is the conversion of the cellular prion protein PrPC into the pathological PrPSc isoform, which aggregate into large protein aggregates. This formation of PrPSc aggregates is a hallmark of the pathogenesis of prion diseases. The available evidence suggests that PrPSc acts both as a template for this conversion and as a neurotoxic agent causing neuronal dysfunction and cell death (Prusiner 1998, Giese and Kretzschmar 2001). Therefore, the most promising therapeutic approach for prion diseases is interference with PrPSc amplification. Evidence derived from cell culture and in vivo studies suggests that once formation of PrPSc is inhibited, clearance of PrPSc can take place (Mallucci 2003). Thus, this therapeutic strategy could also be effective late in the incubation period and even after manifestation of clinical signs of disease, which is essential to be of use in addressing human prion disease.
There are a number of compounds which have been shown to be effective in interfering with PrPSc amplification in vitro such as acridin derivatives, Congo Red, porphyrins/phthalocyanines, Cp-60, beta-sheet breaker peptides and variants of PrP (Caughey et al. 1998, Chabry et al. 1998, Demaimay et al. 2000, Horiuchi et al. 2000, Perrier et al. 2000, Rudyk et al. 2000, Soto et al. 2000). However, none of these compounds have so far been used successfully for disease treatment or as lead compounds for developing compounds with increased therapeutic potency and pharmacological properties.
The substances identified so far as potential therapeutics have mainly been discovered by chance. Few in vitro assays suitable for high-throughput screening of large compound libraries for potential anti-prion drugs have been established so far. Two different approaches for systematic screening have been proposed in recently published studies: one being yeast-based (Bach et al. 2003) and the other using infected ScN2a cell cultures (Kocisko et al. 2004, Kocisko et al. 2003). However, these approaches allowed the screening of libraries limited to 2500 and 2000 compounds, respectively, and turned out to be time-consuming.
In addition to low molecular weight substances, three further potential approaches are tested currently. First, antibodies against PrP are being used to suppress the formation of PrPSc. This method has successfully been used in cell culture as well as in mice injected intraperitoneally (Enari et al., 2001; White et al., 2003). Another approach is the application of CpG oligonucleotides, which where found to increase the incubation period in scrapie-infected mice (Sethi et al., 2002). However, the mechanism of action of this method has not been elucidated so far. Finally, suppression of the expression of PrPC in neurons of infected animals or humans by siRNA is under discussion. This method has been shown to inhibit PrPSc formation in cell cultures (Daude et al., 2003). All three methods face the same problem, namely passage of the molecules through the blood-brain barrier. Due to this drawback, these approaches are only suitable for post exposition prophylaxis in peripheral organs but not for therapy of the disease in the central nervous system.
Another class of neurodegenerative diseases, the so-called synucleinopathies are characterized by intracellular accumulation of protein aggregates, oligomers, protofibrils and fibrils, containing mainly α-synuclein. In the cases of synucleinopathies it is believed that the pathological effects on nerve cells are induced by the formation of oligomeric aggregates of α-synuclein and the subsequent formation of membrane pores. Examples of synucleinopathies are Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). So far, no therapeutic strategies are available for the inhibition of aggregation of α-synuclein.
Hence, there is a need to identify novel compounds suitable for the treatment of diseases linked to aggregating proteins, such as prion diseases and synucleinopathies.
Thus, the technical problem underlying the present invention is the provision of compounds for treating prion diseases, synucleinopathies and other diseases characterized by aggregating proteins, in particular Parkinson's disease. Furthermore, there is a need to provide compounds which are suitable probes for imaging deposits of aggregated proteins in the above mentioned disorders.